Methods of using IL-1 antagonists to treat neointimal hyperplasia

ABSTRACT

Methods of using interleukin-1 (IL-1) antagonists to prevent or treat restenosis and other neointimal hyperplasia conditions, including atherosclerosis, vascular access dysfunction, hypertension and related vascular diseases are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 USC § 119(e) of U.S. Provisional 60/468,232 filed 6 May 2003, which application is herein specifically incorporated by reference in its entirety.

BACKGROUND

[0002] 1. Field of the Invention

[0003] The invention relates to methods of using interleukin-1 (IL-1) antagonists to treat neointimal hyperplasia. In particular, the field of the invention is methods of treating restenosis and other neointimal hyperplasia conditions, including atherosclerosis, venous grafts of fistulae for hemodialysis, also known as vascular access dysfunction, bypass vein grafts, balloon angioplasty, hypertension, and related vascular diseases, using antagonists of IL-1-mediated biological activity.

[0004] 2. Description of Related Art

[0005] Neointimal hyperplasia is the major complication associated with the progression of atherosclerotic plaques, chronic hypertension, and the injury response caused by surgical procedures treating vascular diseases, such as angioplasty and stenting. The activation of smooth muscle cells residing in the vessel wall stimulates their proliferation and migration into the intima area where they narrow the blood vessel and limit blood supply to the affected region. Surgical procedures to remove the neointima (endarterectomy) or to insert a solid support (stenting) have been the most effective treatments to correct the deficiency. Nonetheless, physical injury during these surgical procedures tends to accelerate neointima formation and cause the re-narrowing of the vessel, a process termed restenosis.

[0006] Tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1) are inflammatory cytokines that stimulate expression of adhesion molecules and induce the synthesis of other pro-inflammatory cytokines. TNFα and IL-1 are also known to influence vascular smooth muscle cell migration and proliferation in vitro. Rectenwald et al. (2000) Circulation 102:1697-1702, have shown that TNFα and IL-1 modulate low shear stress-induced neointimal hyperplasia (NIH).

BRIEF SUMMARY OF THE INVENTION

[0007] In a first aspect, the invention features a method of treating, inhibiting, or ameliorating restenosis and other neointimal hyperplasia conditions, including atherosclerosis, vascular access dysfunction, hypertension and related vascular diseases, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. An IL-1 antagonist is a compound capable of blocking or inhibiting the biological action of IL-1, including fusion proteins capable of trapping IL-1, such as an IL-1 trap, interleukin-1 antagonist (IL-1 ra), an anti-IL-1 antibody or fragment thereof, an anti-IL-1 receptor antibody or fragment thereof, a small molecule, or a nucleic acid capable of interfering with the expression of IL-1.

[0008] In a preferred embodiment, the IL-1 antagonist is an IL-1-specific fusion protein comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1 trap described in U.S. patent publication No. 2003/0143697, published 31 Jul. 2003, herein specifically incorporated by reference in its entirety. In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26. A preferred IL-1 trap is shown in SEQ ID NO:10. In another embodiment, the IL-1 antagonist is an antibody or antibody fragment capable of binding IL-1α and/or IL-1β. In another embodiment, the IL-1 antagonist is an anti-IL-1 receptor (IL-1R1 or IL-1 RAcp), or a fragment thereof. In specific embodiments, the IL-1 antagonist is a modified IL-1 trap comprising one or more receptor components and one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor. In another embodiment, the IL-1 antagonist is a modified IL-1 trap comprising one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor. In another embodiment, the IL-1 antagonist is IL-Ira (SEQ ID NO:27 (full-length molecule); SEQ ID NO:28 (mature protein). In yet another embodiment, the IL-1 antagonist is a nucleic acid capable of interfering with the expression of IL-1. Examples of IL-1 antagonist nucleic acids include, for example, antisense molecules, inhibitory ribozymes designed to catalytically cleave gene mRNA transcripts encoding IL-1α, IL-1β, IL-1R1, IL-1RAcp, or short interfering RNA (siRNA) molecules.

[0009] The subject being treated is most preferably a human suffering from or at risk for the development of restenosis and other neointimal hyperplasia conditions, including atherosclerosis, vascular access dysfunction, hypertension and related vascular diseases.

[0010] The method of the invention includes administration of the IL-1 antagonist by any means known to the art, for example, subcutaneous, intramuscular, intranasal, intraarterial, intravenous, topical, transvaginal, transdermal, transanal administration or oral routes of administration.

[0011] In a second aspect, the invention features a method of preventing or inhibiting the development of restenosis in a subject in need thereof, comprising administering an IL-1 antagonist to a subject at risk for or suffering from restenosis, such that development of restenosis or the progression of the disease is inhibited.

[0012] In a third aspect, the invention features a method of preventing or inhibiting the development of atherosclerosis in a subject in need thereof, comprising administering an IL-1 antagonist to a subject at risk for or suffering from atherosclerosis, such that development of atherosclerosis or the progression of the disease is inhibited.

[0013] In a fourth aspect, the invention features a method of preventing or inhibiting the development of vascular access dysfunction in a subject in need thereof, comprising administering an IL-1 antagonist to a subject at risk for or suffering from vascular access dysfunction, such that development of vascular access dysfunction or the progression of the disease is inhibited.

[0014] In a fifth aspect, the invention features a method of inhibiting or ameliorating neointimal hyperplasia caused by hypertension and related vascular diseases, in a subject in need thereof, comprising administering an IL-1 antagonist to a subject at risk for or suffering from neointimal hyperplasia, such that development of neointimal hyperplasia or the progression of the disease is inhibited.

[0015] Accordingly, in a sixth aspect, the invention features pharmaceutical compositions comprising IL-1 antagonists with a pharmaceutically acceptable carrier. Such pharmaceutical compositions may comprise IL-1 traps or anti-IL-1 antibodies, antisense molecules, or siRNAs. The therapeutic methods of the invention may be treated with a combination of one or more IL-1 antagonists and a second therapeutic agent.

[0016] Other objects and advantages will become apparent from a review of the ensuing detailed description.

BRIEF DESCRIPTION OF THE FIGURES

[0017]FIG. 1 shows the inhibitory effect of the IL-1 trap IL-1RAcp-IL-R1-Fc on neointima proliferation. IEL=internal elastic lamina; EEL=external elastic lamina.

[0018]FIG. 2 compares wildtype and IL-1R knockout (KO) animals on neointima proliferation.

[0019]FIGS. 3-4 shows the effect of APOE KO mice transfected with IL-1 trap (FIG. 3) or an Fc control and IL-1R2 trap (FIG. 4).

DETAILED DESCRIPTION

[0020] Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only the appended claims.

[0021] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.

[0023] General Description

[0024] The invention is based in part on the finding that administration of an agent capable of blocking or inhibiting IL-1-mediated biological activity is capable of decreasing, treating or preventing restenosis and other neointimal hyperplasia conditions, including atherosclerosis, vascular access dysfunction, hypertension and related vascular diseases. Thus, the invention provides for methods of decreasing, treating or preventing restenosis and other neointimal hyperplasia conditions in a mammal by administering an IL-1 antagonist, in particular, an IL-1 trap, IL-Ira or anti-IL-1 antibodies.

[0025] Definitions

[0026] By the term “blocker”, “inhibitor”, or “antagonist” is meant a substance that retards or prevents a chemical or physiological reaction or response. Common blockers or inhibitors include but are not limited to antisense molecules, antibodies, antagonists and their derivatives. More specifically, an example of an IL-1 blocker or inhibitor is an IL-1 antagonist including, but not limited to, IL-1 trap.

[0027] By the term “therapeutically effective dose” is meant a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0028] IL-1 Trap Antagonists

[0029] Interleukin-1 (IL-1) traps are multimers of fusion proteins containing IL-1 receptor components and a multimerizing component capable of interacting with the multimerizing component present in another fusion protein to form a higher order structure, such as a dimer. Cytokine traps are a novel extension of the receptor-Fc fusion concept in that they include two distinct receptor components that bind a single cytokine, resulting in the generation of antagonists with dramatically increased affinity over that offered by single component reagents. In fact, the cytokine traps that are described herein are among the most potent cytokine blockers ever described. Briefly, the cytokine traps called IL-1 traps are comprised of the extracellular domain of human IL-1R Type I (IL-1RI) or Type II (IL-1RII) followed by the extracellular domain of human IL-1 Accessory protein (IL-1AcP), followed by a multimerizing component. In a preferred embodiment, the multimerizing component is an immunoglobulin-derived domain, such as, for example, the Fc region of human IgG, including part of the hinge region, the CH2 and CH3 domains. Alternatively, the IL-1 traps are comprised of the extracellular domain of human IL-1 AcP, followed by the extracellular domain of human IL-1RI or IL-1 RII, followed by a multimerizing component. For a more detailed description of the IL-1 traps, see WO 00/18932, which publication is herein specifically incorporated by reference in its entirety. Preferred IL-1 traps have the amino acid sequence shown in SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26.

[0030] In specific embodiments, the IL-1 antagonist comprises an antibody fragment capable of binding IL-1α, IL-1β, IL-1R1 and/or IL-1RAcp, or a fragment thereof. One embodiment of an IL-1 antagonist comprising one or more antibody fragments, for example, single chain Fv (scFv), is described in U.S. Pat. No. 6,472,179, which publication is herein specifically incorporated by reference in its entirety. In all of the IL-1 antagonist embodiments comprising one or more antibody-derived components specific for IL-1 or an IL-1 receptor, the components may be arranged in a variety of configurations, e.g., a IL-1 receptor component(s)—scFv(s)—multimerizing component; IL-1 receptor component(s)—multimerizing component—scFv(s); scFv(s)—IL-1 receptor component(s)—multimerizing component, etc., so long as the molecule or multimer is capable of inhibiting the biological activity of IL-1. In another embodiment, the IL-1 antagonist is IL-Ira, including the full length protein of SEQ ID NO:27 or the mature protein of SEQ ID NO:28. Anti-IL-1 Human Antibodies and Antibody Fragments

[0031] In another embodiment of the IL-1 antagonist useful in the method of the invention, examples of anti-IL-1 antibodies are disclosed in U.S. Pat. No. 4,935,343; U.S. Pat. No. 5,681,933; WO 95/01997; EP 0267611, U.S. Pat. No. 6,419,944; WO 02/16436 and WO 01/53353. The IL-1 antagonist of the invention may include an antibody or antibody fragment specific for an IL-1 ligand (e.g., IL-1α or IL-1β) and/or an IL-1 receptor (e.g., IL-1R1 and/or IL-1RAcp). Antibody fragments include any fragment having the required target specificity, e.g. antibody fragments either produced by the modification of whole antibodies (e.g. enzymatic digestion), or those synthesized de novo using recombinant DNA methodologies (scFv, single domain antibodies or dabs, single variable domain antibodies) or those identified using human phase display libraries (see, for example, McCafferty et al. (1990) Nature 348:552-554). Alternatively, antibodies can be isolated from mice producing human or human-mouse chimeric antibodies using standard immunization and antibody isolation methods, including but not limited to making hybridomas, or using B cell screening technologies, such as SLAM. Immunoglobulin binding domains also include, but are not limited to, the variable regions of the heavy (V_(H)) or the light (V_(L)) chains of immunoglobulins.

[0032] The term “antibody” as used herein refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant regions, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively. Within each IgG class, there are different isotypes (eg. IgG₁, IgG₂, IgG₃, IgG₄). Typically, the antigen-binding region of an antibody will be the most critical in determining specificity and affinity of binding.

[0033] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one light chain (about 25 kD) and one heavy chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100-110 or more amino acids primarily responsible for antigen recognition. The terms “variable light chain” (V_(L)) and variable heavy chain (V_(H)) refer to these light and heavy chains respectively.

[0034] Antibodies exist as intact immunoglobulins, or as a number of well-characterized fragments produced by digestion with various peptidases. For example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′₂, a dimer of Fab which itself is a light chain joined to V_(H)-C_(H)1 by a disulfide bond. The F(ab)′₂ may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)′₂ dimer into an Fab′ monomer. The Fab′ monomer is essentially Fab with part of the hinge region. While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology.

[0035] Methods for preparing antibodies are known to the art. See, for example, Kohler & Milstein (1975) Nature 256:495-497; Harlow & Lane (1988) Antibodies: a Laboratory Manual, Cold Spring Harbor Lab., Cold Spring Harbor, N.Y.). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Monoclonal antibodies can be humanized using standard cloning of the CDR regions into a human scaffold. Gene libraries encoding human heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity. Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Pat. No. 4,946,778; U.S. Pat. No. 4,816,567) can be adapted to produce antibodies used in the fusion proteins and methods of the instant invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express human, human-mouse chimeric, or humanized antibodies. Alternatively, phage display technology can be used to identify human antibodies and heteromeric Fab fragments that specifically bind to selected antigens.

[0036] Antibody Screening and Selection

[0037] Screening and selection of preferred antibodies can be conducted by a variety of methods known to the art. Initial screening for the presence of monoclonal antibodies specific to a target antigen may be conducted through the use of ELISA-based methods, for example. A secondary screen is preferably conducted to identify and select a desired monoclonal antibody for use in construction of the multi-specific fusion proteins of the invention. Secondary screening may be conducted with any suitable method known to the art. One preferred method, termed “Biosensor Modification-Assisted Profiling” (“BiaMAP”) is described in co-pending U.S. Ser. No. 60/423,017 filed 01 Nov. 2002, herein specifically incorporated by reference in its entirety. BiaMAP allows rapid identification of hybridoma clones producing monoclonal antibodies with desired characteristics. More specifically, monoclonal antibodies are sorted into distinct epitope-related groups based on evaluation of antibody:antigen interactions. Antibodies capable of blocking either a ligand or a receptor may be identified by a cell based assay, such as a luciferase assay utilizing a luciferase gene under the control of an NFKB driven promoter. Stimulation of the IL-1 receptors by IL-1 ligands leads to a signal through NFKB thus increasing luciferase levels in the cell. Blocking antibodies are identified as those antibodies that blocked IL-1 induction of luciferase activity.

[0038] Antisense Nucleic Acids

[0039] In a further embodiment, IL-1-mediated biological activity is blocked or inhibited by the use of IL-1 antisense nucleic acids. The present invention provides the therapeutic or prophylactic use of nucleic acids comprising at least six nucleotides that are antisense to the gene or cDNA encoding IL-1α, IL-1β, IL-1R1, or IL-1RAcp or portions thereof. As used herein, IL-1 “antisense” nucleic acids refers to nucleic acids capable of hybridizing by virtue of some sequence complementarity to a portion of an RNA (preferably mRNA) encoding IL-1α, IL-1β, IL-1R1, or IL-1RAcp. The antisense nucleic acids may be complementary to a coding and/or noncoding region of an mRNA encoding IL-1α, IL-1β, IL-1R1, or IL-1RAcp. Such antisense nucleic acids have utility as compounds that prevent IL-1α, IL-1β, IL-1R1, or IL-1RAcp expression, and can be used in the prevention or treatment of restenosis and other neointimal hyperplasia conditions, including atherosclerosis, vascular access dysfunction, hypertension and related vascular diseases. The antisense nucleic acids of the invention are double-stranded or single-stranded oligonucleotides, RNA or DNA or a modification or derivative thereof, and can be directly administered to a cell or produced intracellularly by transcription of exogenous, introduced sequences.

[0040] The invention further provides pharmaceutical compositions comprising a therapeutically effective amount of IL-1α, IL-1β, IL-1R1, or IL-1RAcp antisense nucleic acids, and a pharmaceutically acceptable carrier, vehicle or diluent.

[0041] The IL-1α, IL-1β, IL-1R1, or IL-1RAcp antisense nucleic acids are of at least six nucleotides and are preferably oligonucleotides ranging from 6 to about 50 oligonucleotides. In specific aspects, the oligonucleotide is at least 10 nucleotides, at least 15 nucleotides, at least 100 nucleotides, or at least 200 nucleotides. The oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof and can be single-stranded or double-stranded.

[0042] Short Interfering RNAs

[0043] In another embodiment, IL-1α, IL-1β, IL-1R1, or IL-1RAcp expression is inhibited by a short interfering RNA (siRNA) through RNA interference (RNAi) or post-transcriptional gene silencing (PTGS) (see, for example, Ketting et al. (2001) Genes Develop. 15:2654-2659). siRNA molecules can target homologous mRNA molecules for destruction by cleaving the mRNA molecule within the region spanned by the siRNA molecule. Accordingly, siRNAs capable of targeting and cleaving homologous IL-1α, IL-1β, IL-1R1, or IL-1RAcp mRNA are useful for preventing or treating restenosis and other neointimal hyperplasia conditions, including atherosclerosis, vascular access dysfunction, hypertension and related vascular diseases.

[0044] Inhibitory Ribozymes

[0045] In another embodiment, restenosis and other neointimal hyperplasia conditions, including atherosclerosis, vascular access dysfunction, hypertension and related vascular diseases may be treated in a subject suffering from such diseases or disorders by decreasing the level of IL-1-mediated biological activity by using ribozyme molecules designed to catalytically cleave gene mRNA transcripts encoding IL-1α, IL-1β, IL-1R1, or IL-1RAcp, preventing translation of target gene mRNA and, therefore, expression of the gene product.

[0046] Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by an endonucleolytic cleavage event. The composition of ribozyme molecules must include one or more sequences complementary to the target gene mRNA, and must include the well known catalytic sequence responsible for mRNA cleavage. For this sequence, see, e.g., U.S. Pat. No. 5,093,246. While ribozymes that cleave mRNA at site-specific recognition sequences can be used to destroy mRNAs encoding IL-1α, IL-1β, IL-1R1, or IL-1RAcp, the use of hammerhead ribozymes is preferred. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions that form complementary base pairs with the target mRNA. The sole requirement is that the target mRNA has the following sequence of two bases: 5′-UG-3′. The construction and production of hammerhead ribozymes is well known in the art. The ribozymes of the present invention also include RNA endoribonucleases (hereinafter “Cech-type ribozymes”) such as the one that occurs naturally in Tetrahymena thermophila (known as the IVS, or L-19 IVS RNA). The Cech-type ribozymes have an eight base pair active site that hybridizes to a target RNA sequence where after cleavage of the target RNA takes place. The invention encompasses those Cech-type ribozymes that target eight base-pair active site sequences that are present in the genes encoding IL-1α, IL-1β, IL-1R1, or IL-1RAcp.

[0047] Standard methods for assessing cardiovascular health can be used to determine whether a subject is positively responding to treatment with the IL-1 antagonists. For example, after treatment with a IL-1 cytokine antagonist of the invention, a physician may choose to administer a stress test to determine that the subject is benefiting from administration of the cytokine antagonist. Generally the physician will monitor the patients activity level and general health to assess whether the subject is benefiting from administration of the cytokine antagonist. Thus, these as well as other methods known to the art, may be used to determine the extent to which the methods of the present invention are effective at treating neointimal hyperplasia including restenosis.

[0048] Treatment Population

[0049] Treatment population would include those people with vascular diseases being treated with coronary bypass surgery, angioplasty treatment, treatment with stents or drug coated stents; hemodialysis patients requiring grafts or fistulae; patients with elevated CRP levels with a history of vascular disease or atherosclerosis; patients diagnosed with peripheral vascular disease or hypertension; patients diagnosed with Buerger's disease, critical limb ischemia or thromboangiitis obliterans; patients undergoing vascular surgery for example, varicose veins, aneurysms, or arotic dissection.

[0050] Methods of Administration

[0051] The invention provides methods of treatment comprising administering to a subject an effective amount of an agent of the invention. In a preferred aspect, the agent is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject is preferably an animal, e.g., such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human.

[0052] Various delivery systems are known and can be used to administer an agent of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction can be enteral or parenteral and include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.

[0053] In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; this may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, fibers, commercial skin substitutes or angioplasty balloons or stents.

[0054] In another embodiment, the active agent can be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533). In yet another embodiment, the active agent can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer (1990) supra). In another embodiment, polymeric materials can be used (see Howard et al. (1989) J. Neurosurg. 71:105). In another embodiment where the active agent of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see, for example, U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.

[0055] Cellular Transfection and Gene Therapy

[0056] The present invention encompasses the use of nucleic acids encoding the IL-1-specific fusion proteins of the invention for transfection of cells in vitro and in vivo. These nucleic acids can be inserted into any of a number of well-known vectors for transfection of target cells and organisms. The nucleic acids are transfected into cells ex vivo and in vivo, through the interaction of the vector and the target cell. Reintroduction of transfected cells may be accomplished by any method known to the art, including re-implantation of encapsulated cells. The compositions are administered (e.g., by injection into a muscle) to a subject in an amount sufficient to elicit a therapeutic response. An amount adequate to accomplish this is defined as “a therapeutically effective dose or amount.”

[0057] In another aspect, the invention provides a method of treating or preventing neointimal hyperplasia in a human comprising transfecting a cell with a nucleic acid encoding an IL-1-specific fusion protein of the invention, antibody or IL-Ira, wherein the nucleic acid comprises an inducible promoter operably linked to the nucleic acid encoding the IL-1-specific fusion protein antibody or IL-Ira. For gene therapy procedures in the treatment or prevention of human disease, see for example, Van Brunt (1998) Biotechnology 6:1149-1154.

[0058] Combination Therapies

[0059] In numerous embodiments, the IL-1 antagonists of the present invention may be administered in combination with one or more additional compounds or therapies or surgical procedures. For example, a suitable therapeutic agent for use in combination, either alternating or simultaneously, with the IL-1 antagonists may include anti-platelet therapy such as aspirin, Reopro™ (Lilly), anti-p-selectin antibodies; antithrombolic and blood thinning agents, such as Retavse™ (Centocor); Streptase™ (AstraZeneca), TNKase™ (Genentech), Ticlid™ (Roche) and Plavix™ (Bristol-Myers Squibb) and heparin; HMG-CoA reductase inhibitors, such as Baycol™ (Bayer), Lescol™ (Noavartis), Lipitor™ (Pfizer), Mevacor™ (Merck), Pravachol™ (Bristol Myers Squibb, Zocor™ (Merck) or antilipidemic agents such as, Colestid™ (Pfizer), WelChol™ (Sankyo), Atromid-S™ (Wyeth), Lopid™ (Pfizer), Tricor™ (Abbott); agents effective to treat or prevent restenosis such as Sirolimus™ (Wyeth, Johnson & Johnson), dexamethasone (Merck), Predisolone™ (Muro, Mylan, Watson, We), Tacrolimus™ (Fujisawa), Pimecrolimus™ (Novartis) Taxol/Paclitaxel (Bristol-Myers Squibb), or Methotrexate (Baxter, Mylan, Roxane); anti-fibrolytic agents such as antibodies against TGFB PDGF, or CTGF; PDGF inhibitors such as Gleevec™ (Novartis); anti-inflammatory agents such as antibodies, peptides and other inhibitors of CD11a/CD8 (Mac 1) [Raptiva™ (Genentech)], ICAM, C5a and TNFα [Humira™ (Abbott), Enbrel™ (Amgen), Remicade™ (Centocor)], Thalidomide™ (Celltech); hypertension drugs, such as ACE inhibitors [Accupril™ (Parke-Davis); Altace™ (Monarch); Captopril™ (Mylan); Enalaprilate™ (Baxter); Lotensin™ (Novartis); Mavik™ (Bristol-Myers Squibb); Prinivil™ (Merck); Univasc™ (Schwarz), Vasotec™ (Merck)]. In addition the IL-1 antagonists may be used in combination, either alternating or simultaneously, with surgical procedures including but not limited to surgical stenting and balloon angioplasty.

[0060] Pharmaceutical Compositions

[0061] The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an active agent, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.

[0062] In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0063] The active agents of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

[0064] The amount of the active agent of the invention which will be effective in the treatment of delayed-type hypersensitivity can be determined by standard clinical techniques based on the present description. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances. However, suitable dosage ranges for intravenous administration are generally about 20 micrograms to 2 grams of active compound per kilogram body weight. Suitable dosage ranges for intra-nasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0065] For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC₅₀ as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data, e.g., animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.

[0066] Dosage amount and interval may be adjusted individually to provide plasma levels of the compounds that are sufficient to maintain therapeutic effect. In cases of local administration or selective uptake, the effective local concentration of the compounds may not be related to plasma concentration. One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

[0067] The amount of compound administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. The therapy may be repeated intermittently while symptoms are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs.

[0068] Kits

[0069] The invention also provides an article of manufacturing comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises at least one IL-1-specific fusion protein of the invention and wherein the packaging material comprises a label or package insert which indicates that the IL-1-specific fusion protein can be used for treating neointimal hyperplasia.

[0070] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

[0071] The following example is put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

Example 1 Experimental protocol and surgical procedures

[0072] Animals: C57B16 mice, interleukin-1 receptor type I deficient (IL-1RI −/−) mice and apolipoprotein E deficient (APOE −/−) mice at the age of 8 to 12 weeks were used in this study to assess vascular response to injury. Both of the genetically modified mice are congenic to the C57B16 background. All animals were purchased from Jackson Laboratories (Bar Harbor, Me.). Mice were housed in individual cages after surgery and were allowed ad libitum access to regular chow and water.

[0073] Vascular injury model: Vascular injury was induced by surgical ligation of the left common carotid artery before bifurcation. Mice were anesthetized by intraperitoneal injection of a Ketamine/xylazine solution. After anesthesia was attained, a midline incision was made at the tracheal area from the caudal end of the larynx to the suprasternal notch. After separating the sternothyroideus muscle on the left side, the pulsating carotid artery was identified and ligated with sterile 6-0 silk sutures. The skin was closed with sterile sutures.

[0074] Delivery of murine IL-1 trap: Expression of murine IL-1 trap was introduced using a hydrodynamics-based administration of plasmid DNA via tail vein injection. Four days prior to surgery, animals were divided equally into two groups. One group of mice received 50-100 μg/animal plasmid DNA carrying the murine IL-1 trap expression vector. The other group of mice received an equal amount of empty control vector DNA. Mice were anesthetized using Isoflurane™. Plasmid DNA diluted in sterile saline in an amount equivalent to 10% (V/W) of the mouse body weight was injected promptly into tail vein.

[0075] Tissue harvesting and preparation: Twenty-eight days after carotid artery ligation, the mice were anesthetized and whole blood was collected from each mouse through cardiac puncture. Subsequently, mice were perfused with saline followed by 10% neutral buffered formalin through the left cardiac ventricle. The entire neck section was collected from each mouse and post-fixed in 10% formalin for an additional 48 hours. Fixed neck tissue was decalcified in 10% EDTA solution for 8 days with frequent changes of fresh solution. Decalcified neck tissue were embedded in gelatin by sequential incubation in 5%, 10% and 25% gelatin solution and prepared for cryosection. Ligation sites were identified by suture position. Seven successive 10 mm sections at 500 mm intervals proximal to the ligation site were used for morphometric analysis per mouse.

[0076] Morphometry: Cryosections were stained with standard hematoxylin and eosin methodology. The images of injured arteries and contra-lateral uninjured arteries were captured using a Nikon Microphot microscope and SPOT software and a SPOT RT COLOR camera. The length encircling the lumen, the internal elastic lamina (IEL) and the external elastic lamina (EEL) was determined by digitally tracing the perimeter of each layer using Bersoft Image Measurement 2.01 software. The length was then converted to circumference assuming the native artery formed a circular structure to calculate the area. The neointima area was defined as the difference between the areas of lumen and IEL. The thickness of media was calculated as the difference of radius between IEL and EEL.

[0077] Results. A mouse vascular injury model was used to investigate factors mediating the formation of neointima. The left common carotid artery of C57Bl/6 mouse was surgically ligated at the position before the bifurcation. The occlusion of the common carotid artery stimulates significant neointima formation proximal to the ligation site over a four week period. Interleukin-1b appears to play an important role in this response because (1) the expression of interleukin-1b is substantially increased under the injury condition and (2) the neointima formation is suppressed in a genetically engineered mouse lacking the signal transducing receptor of interleukin-1 (IL-1R1 knockout mouse) (Rectenwald (2000) Circulation 102:1967-1702). However, IL-1a may also play a role, thus the IL-1 traps are a superior method of blocking the resposne over those that block only a single IL-1 ligand.

[0078] To examine if the interleukin-1 antagonist IL-1 trap can inhibit neointima formation, IL-1 trap IL-1RAcp-IL-1R1-Fc trap expressed in vivo using a hydrodynamic-based transfection method with plasmid DNA vector four days prior to the surgery. Half of C57Bl/6 mice (N=10) received plasmid DNA carrying an IL-1 trap expression vectors. Others were injected with empty control vector DNA. Four weeks after surgical injury, mice were sacrificed for subsequent analyses. Histological examination of the injured vessels revealed that the neointima formation was completely blocked in IL-1 trap-expressing animals, whereas the arteries from the vector control group revealed a significant accumulation of cells under the endothelial cell layer. Morphometric quantitation of the common carotid arteries over a 3.5 mm length demonstrated the inhibitory effect of the IL-1 Racp-IL-1R1-Fc trap in neointima proliferation (FIG. 1). The neointimal growth is determined as the area between the IEL, and the lumen and thus is the difference between the IEL and Lumen radii. The effect of the lack of IL-1R1 in knockout mice is shown in FIG. 2. Similar reductions on neointimal growth were seen in the trap-treated mice as were seen in the IL-1R1 knockout indicating the IL-1 trap has an effect similar to a complete blockade of IL-1 signaling.

[0079] APOE is a surface protein of serum lipoprotein particles whose deficiency results in hypercholesterolemia and spontaneous atherosclerotic plaque formation in APOE knockout mice. APOE deficiency also exacerbates arterial injury causing increased neointima formation with necrotic cores similar to advanced fibroatheroma. To test if the IL-1 trap could prevent the neointima formation under APOE-deficient conditions, APOE knockout mice were transfected with either an IL-1RAcp-IL-1R1-Fc or IL-1 Acrp-IL-1R2-Fc trap expression vector or an Fc control vector before surgical injury. At 28 days after surgical injury, it was found that the IL-1 trap treatments caused a 85% reduction of neointima area including the fibrous cap (FIGS. 3 and 4). This confirms that the IL-1 Traps are potent blockers of neointima formation under hypercholesterolemia condition.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 28 <210> SEQ ID NO 1 <211> LENGTH: 2733 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 atg gtg ctt ctg tgg tgt gta gtg agt ctc tac ttt tat gga atc ctg 48 caa agt gat gcc tca gaa cgc tgc gat gac tgg gga cta gac acc atg 96 agg caa atc caa gtg ttt gaa gat gag cca gct cgc atc aag tgc cca 144 ctc ttt gaa cac ttc ttg aaa ttc aac tac agc aca gcc cat tca gct 192 ggc ctt act ctg atc tgg tat tgg act agg cag gac cgg gac ctt gag 240 gag cca att aac ttc cgc ctc ccc gag aac cgc att agt aag gag aaa 288 gat gtg ctg tgg ttc cgg ccc act ctc ctc aat gac act ggc aac tat 336 acc tgc atg tta agg aac act aca tat tgc agc aaa gtt gca ttt ccc 384 ttg gaa gtt gtt caa aaa gac agc tgt ttc aat tcc ccc atg aaa ctc 432 cca gtg cat aaa ctg tat ata gaa tat ggc att cag agg atc act tgt 480 cca aat gta gat gga tat ttt cct tcc agt gtc aaa ccg act atc act 528 tgg tat atg ggc tgt tat aaa ata cag aat ttt aat aat gta ata ccc 576 gaa ggt atg aac ttg agt ttc ctc att gcc tta att tca aat aat gga 624 aat tac aca tgt gtt gtt aca tat cca gaa aat gga cgt acg ttt cat 672 ctc acc agg act ctg act gta aag gta gta ggc tct cca aaa aat gca 720 gtg ccc cct gtg atc cat tca cct aat gat cat gtg gtc tat gag aaa 768 gaa cca gga gag gag cta ctc att ccc tgt acg gtc tat ttt agt ttt 816 ctg atg gat tct cgc aat gag gtt tgg tgg acc att gat gga aaa aaa 864 cct gat gac atc act att gat gtc acc att aac gaa agt ata agt cat 912 agt aga aca gaa gat gaa aca aga act cag att ttg agc atc aag aaa 960 gtt acc tct gag gat ctc aag cgc agc tat gtc tgt cat gct aga agt 1008 gcc aaa ggc gaa gtt gcc aaa gca gcc aag gtg aag cag aaa gtg cca 1056 gct cca aga tac aca gtg tcc ggt ggc gcg cct atg ctg agc gag gct 1104 gat aaa tgc aag gaa cgt gaa gaa aaa ata att tta gtg tca tct gca 1152 aat gaa att gat gtt cgt ccc tgt cct ctt aac cca aat gaa cac aaa 1200 ggc act ata act tgg tat aag gat gac agc aag aca cct gta tct aca 1248 gaa caa gcc tcc agg att cat caa cac aaa gag aaa ctt tgg ttt gtt 1296 cct gct aag gtg gag gat tca gga cat tac tat tgc gtg gta aga aat 1344 tca tct tac tgc ctc aga att aaa ata agt gca aaa ttt gtg gag aat 1392 gag cct aac tta tgt tat aat gca caa gcc ata ttt aag cag aaa cta 1440 ccc gtt gca gga gac gga gga ctt gtg tgc cct tat atg gag ttt ttt 1488 aaa aat gaa aat aat gag tta cct aaa tta cag tgg tat aag gat tgc 1536 aaa cct cta ctt ctt gac aat ata cac ttt agt gga gtc aaa gat agg 1584 ctc atc gtg atg aat gtg gct gaa aag cat aga ggg aac tat act tgt 1632 cat gca tcc tac aca tac ttg ggc aag caa tat cct att acc cgg gta 1680 ata gaa ttt att act cta gag gaa aac aaa ccc aca agg cct gtg att 1728 gtg agc cca gct aat gag aca atg gaa gta gac ttg gga tcc cag ata 1776 caa ttg atc tgt aat gtc acc ggc cag ttg agt gac att gct tac tgg 1824 aag tgg aat ggg tca gta att gat gaa gat gac cca gtg cta ggg gaa 1872 gac tat tac agt gtg gaa aat cct gca aac aaa aga agg agt acc ctc 1920 atc aca gtg ctt aat ata tcg gaa att gag agt aga ttt tat aaa cat 1968 cca ttt acc tgt ttt gcc aag aat aca cat ggt ata gat gca gca tat 2016 atc cag tta ata tat cca gtc act aat tcc gga gac aaa act cac aca 2064 tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga ccg tca gtc ttc 2112 ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc tcc cgg acc cct 2160 gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa gac cct gag gtc 2208 aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat aat gcc aag aca 2256 aag ccg cgg gag gag cag tac aac agc acg tac cgt gtg gtc agc gtc 2304 ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag gag tac aag tgc 2352 aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag aaa acc atc tcc 2400 aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac acc ctg ccc cca 2448 tcc cgg gag gag atg acc aag aac cag gtc agc ctg acc tgc ctg gtc 2496 aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg gag agc aat ggg 2544 cag ccg gag aac aac tac aag acc acg cct ccc gtg ctg gac tcc gac 2592 ggc tcc ttc ttc ctc tat agc aag ctc acc gtg gac aag agc agg tgg 2640 cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat gag gct ctg cac 2688 aac cac tac acg cag aag agc ctc tcc ctg tct ccg ggt aaa 2730 tga 2733 <210> SEQ ID NO 2 <211> LENGTH: 910 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val Ser Gly Gly Ala Pro Met Leu Ser Glu Ala 355 360 365 Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val Ser Ser Ala 370 375 380 Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn Glu His Lys 385 390 395 400 Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro Val Ser Thr 405 410 415 Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu Trp Phe Val 420 425 430 Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val Val Arg Asn 435 440 445 Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe Val Glu Asn 450 455 460 Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys Gln Lys Leu 465 470 475 480 Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met Glu Phe Phe 485 490 495 Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr Lys Asp Cys 500 505 510 Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val Lys Asp Arg 515 520 525 Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn Tyr Thr Cys 530 535 540 His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile Thr Arg Val 545 550 555 560 Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg Pro Val Ile 565 570 575 Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly Ser Gln Ile 580 585 590 Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile Ala Tyr Trp 595 600 605 Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val Leu Gly Glu 610 615 620 Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg Ser Thr Leu 625 630 635 640 Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe Tyr Lys His 645 650 655 Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp Ala Ala Tyr 660 665 670 Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Gly Asp Lys Thr His Thr 675 680 685 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 690 695 700 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 705 710 715 720 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 725 730 735 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 740 745 750 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 755 760 765 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 770 775 780 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 785 790 795 800 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 805 810 815 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 820 825 830 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 835 840 845 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 850 855 860 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 865 870 875 880 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 885 890 895 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 900 905 910 <210> SEQ ID NO 3 <211> LENGTH: 2703 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60 aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120 cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180 agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240 tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300 tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360 tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420 tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480 aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540 atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600 tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660 aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720 tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780 tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840 gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900 gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960 gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020 ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080 ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140 atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200 gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260 actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320 ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380 ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440 tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500 aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560 aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620 ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680 aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740 tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800 cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860 gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920 agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980 cagaaagtgc cagctccaag atacacagtg gaatccggag acaaaactca cacatgccca 2040 ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400 gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 2460 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctat 2580 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700 tga 2703 <210> SEQ ID NO 4 <211> LENGTH: 900 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser 1 5 10 15 Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val 20 25 30 Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn 35 40 45 Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro 50 55 60 Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu 65 70 75 80 Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val 85 90 95 Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe 100 105 110 Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys 115 120 125 Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met 130 135 140 Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr 145 150 155 160 Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val 165 170 175 Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn 180 185 190 Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile 195 200 205 Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg 210 215 220 Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly 225 230 235 240 Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile 245 250 255 Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val 260 265 270 Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg 275 280 285 Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe 290 295 300 Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp 305 310 315 320 Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys 325 330 335 Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 340 345 350 Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 355 360 365 Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 370 375 380 Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 385 390 395 400 Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 405 410 415 Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 420 425 430 Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 435 440 445 Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 450 455 460 Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 465 470 475 480 Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 485 490 495 Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 500 505 510 Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 515 520 525 Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 530 535 540 Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 545 550 555 560 Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 565 570 575 Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 580 585 590 Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 595 600 605 Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 610 615 620 Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 625 630 635 640 Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 645 650 655 Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser 660 665 670 Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 675 680 685 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 690 695 700 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 705 710 715 720 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 725 730 735 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 740 745 750 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 755 760 765 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 770 775 780 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 785 790 795 800 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 805 810 815 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 820 825 830 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 835 840 845 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 850 855 860 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 865 870 875 880 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 885 890 895 Ser Pro Gly Lys 900 <210> SEQ ID NO 5 <211> LENGTH: 2709 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5 atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60 aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120 cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180 agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240 tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300 tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360 tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420 tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480 aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540 atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600 tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660 aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720 tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780 tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840 gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900 gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960 gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020 ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080 ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140 atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200 gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260 actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320 ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380 ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440 tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500 aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560 aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620 ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680 aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740 tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800 cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860 gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920 agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980 cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040 tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100 aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160 gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220 aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280 ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340 aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400 ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460 acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580 ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640 tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700 ggtaaatga 2709 <210> SEQ ID NO 6 <211> LENGTH: 902 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser 1 5 10 15 Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val 20 25 30 Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn 35 40 45 Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro 50 55 60 Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu 65 70 75 80 Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val 85 90 95 Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe 100 105 110 Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys 115 120 125 Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met 130 135 140 Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr 145 150 155 160 Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val 165 170 175 Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn 180 185 190 Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile 195 200 205 Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg 210 215 220 Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly 225 230 235 240 Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile 245 250 255 Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val 260 265 270 Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg 275 280 285 Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe 290 295 300 Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp 305 310 315 320 Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys 325 330 335 Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 340 345 350 Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 355 360 365 Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 370 375 380 Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 385 390 395 400 Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 405 410 415 Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 420 425 430 Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 435 440 445 Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 450 455 460 Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 465 470 475 480 Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 485 490 495 Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 500 505 510 Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 515 520 525 Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 530 535 540 Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 545 550 555 560 Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 565 570 575 Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 580 585 590 Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 595 600 605 Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 610 615 620 Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 625 630 635 640 Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 645 650 655 Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser 660 665 670 Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu 675 680 685 Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 705 710 715 720 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 785 790 795 800 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 865 870 875 880 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895 Ser Leu Ser Leu Gly Lys 900 <210> SEQ ID NO 7 <211> LENGTH: 2709 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60 aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120 cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180 agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240 tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300 tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360 tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420 tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480 aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540 atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600 tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660 aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720 tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780 tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840 gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900 gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960 gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020 ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080 ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140 atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200 gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260 actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320 ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380 ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440 tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500 aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560 aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620 ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680 aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740 tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800 cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860 gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920 agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980 cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040 tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100 aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160 gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220 aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280 ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340 aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400 ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460 acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580 ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640 tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700 ggtaaatga 2709 <210> SEQ ID NO 8 <211> LENGTH: 902 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser 1 5 10 15 Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val 20 25 30 Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn 35 40 45 Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro 50 55 60 Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu 65 70 75 80 Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val 85 90 95 Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe 100 105 110 Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys 115 120 125 Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met 130 135 140 Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr 145 150 155 160 Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val 165 170 175 Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn 180 185 190 Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile 195 200 205 Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg 210 215 220 Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly 225 230 235 240 Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile 245 250 255 Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val 260 265 270 Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg 275 280 285 Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe 290 295 300 Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp 305 310 315 320 Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys 325 330 335 Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 340 345 350 Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 355 360 365 Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 370 375 380 Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 385 390 395 400 Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 405 410 415 Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 420 425 430 Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 435 440 445 Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 450 455 460 Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 465 470 475 480 Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 485 490 495 Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 500 505 510 Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 515 520 525 Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 530 535 540 Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 545 550 555 560 Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 565 570 575 Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 580 585 590 Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 595 600 605 Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 610 615 620 Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 625 630 635 640 Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 645 650 655 Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser 660 665 670 Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 675 680 685 Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 705 710 715 720 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 785 790 795 800 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 865 870 875 880 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895 Ser Leu Ser Leu Gly Lys 900 <210> SEQ ID NO 9 <211> LENGTH: 2703 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60 tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120 gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180 gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240 gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300 ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360 tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420 cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480 ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540 tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600 attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660 cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720 gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780 gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840 tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900 agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960 gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020 gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080 tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140 ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200 aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260 tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320 tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380 aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440 ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500 gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560 gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620 ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680 cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740 cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800 aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860 aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920 agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980 gcatatatcc agttaatata tccagtcact aattccggag acaaaactca cacatgccca 2040 ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400 gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 2460 ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 2580 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700 tga 2703 <210> SEQ ID NO 10 <211> LENGTH: 900 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile 355 360 365 Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu 370 375 380 Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser 385 390 395 400 Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys 405 410 415 Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr 420 425 430 Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser 435 440 445 Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala 450 455 460 Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys 465 470 475 480 Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu 485 490 495 Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe 500 505 510 Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His 515 520 525 Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln 530 535 540 Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys 545 550 555 560 Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val 565 570 575 Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu 580 585 590 Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp 595 600 605 Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn 610 615 620 Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu 625 630 635 640 Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His 645 650 655 Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser 660 665 670 Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 675 680 685 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 690 695 700 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 705 710 715 720 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 725 730 735 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 740 745 750 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 755 760 765 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 770 775 780 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 785 790 795 800 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 805 810 815 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 820 825 830 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 835 840 845 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 850 855 860 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 865 870 875 880 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 885 890 895 Ser Pro Gly Lys 900 <210> SEQ ID NO 11 <211> LENGTH: 2709 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60 tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120 gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180 gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240 gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300 ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360 tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420 cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480 ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540 tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600 attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660 cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720 gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780 gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840 tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900 agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960 gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020 gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080 tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140 ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200 aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260 tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320 tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380 aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440 ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500 gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560 gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620 ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680 cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740 cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800 aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860 aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920 agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980 gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040 tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100 aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160 gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220 aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280 ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340 aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400 ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460 acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580 ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640 tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700 ggtaaatga 2709 <210> SEQ ID NO 12 <211> LENGTH: 902 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile 355 360 365 Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu 370 375 380 Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser 385 390 395 400 Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys 405 410 415 Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr 420 425 430 Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser 435 440 445 Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala 450 455 460 Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys 465 470 475 480 Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu 485 490 495 Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe 500 505 510 Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His 515 520 525 Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln 530 535 540 Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys 545 550 555 560 Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val 565 570 575 Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu 580 585 590 Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp 595 600 605 Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn 610 615 620 Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu 625 630 635 640 Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His 645 650 655 Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser 660 665 670 Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu 675 680 685 Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 705 710 715 720 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 785 790 795 800 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 865 870 875 880 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895 Ser Leu Ser Leu Gly Lys 900 <210> SEQ ID NO 13 <211> LENGTH: 2709 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60 tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120 gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180 gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240 gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300 ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360 tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420 cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480 ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540 tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600 attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660 cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720 gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780 gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840 tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900 agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960 gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020 gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080 tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140 ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200 aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260 tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320 tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380 aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440 ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500 gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560 gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620 ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680 cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740 cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800 aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860 aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920 agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980 gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040 tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100 aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160 gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220 aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280 ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340 aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400 ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460 acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580 ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640 tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700 ggtaaatga 2709 <210> SEQ ID NO 14 <211> LENGTH: 902 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile 355 360 365 Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu 370 375 380 Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser 385 390 395 400 Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys 405 410 415 Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr 420 425 430 Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser 435 440 445 Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala 450 455 460 Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys 465 470 475 480 Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu 485 490 495 Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe 500 505 510 Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His 515 520 525 Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln 530 535 540 Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys 545 550 555 560 Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val 565 570 575 Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu 580 585 590 Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp 595 600 605 Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn 610 615 620 Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu 625 630 635 640 Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His 645 650 655 Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser 660 665 670 Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu 675 680 685 Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 690 695 700 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 705 710 715 720 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 725 730 735 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 740 745 750 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 755 760 765 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 770 775 780 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 785 790 795 800 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 805 810 815 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 820 825 830 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 835 840 845 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg 850 855 860 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 865 870 875 880 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 885 890 895 Ser Leu Ser Leu Gly Lys 900 <210> SEQ ID NO 15 <211> LENGTH: 2748 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60 cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120 ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180 gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240 gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300 gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360 attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420 attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480 gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540 gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600 gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660 actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720 tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780 tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840 atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900 aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960 cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020 gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080 aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140 ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200 actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260 agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320 acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380 caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440 tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500 ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560 gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620 gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680 gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740 gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800 ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860 actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920 actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980 catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040 gctccaagat acacagtgtc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100 gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160 atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220 gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280 gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340 tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400 gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460 ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520 tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580 accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640 gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700 cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748 <210> SEQ ID NO 16 <211> LENGTH: 915 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu 1 5 10 15 Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly 20 25 30 Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu 35 40 45 Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg 50 55 60 Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly 65 70 75 80 Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu 85 90 95 Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn 100 105 110 Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn 115 120 125 Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu 130 135 140 Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg 145 150 155 160 Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu 165 170 175 Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu 180 185 190 Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val 195 200 205 Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile 210 215 220 Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile 225 230 235 240 Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile 245 250 255 Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu 260 265 270 Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly 275 280 285 Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn 290 295 300 Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu 305 310 315 320 His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr 325 330 335 Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys 340 345 350 Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 355 360 365 Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 370 375 380 Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 385 390 395 400 Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 405 410 415 Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 420 425 430 Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 435 440 445 Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 450 455 460 Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 465 470 475 480 Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 485 490 495 Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 500 505 510 Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 515 520 525 Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 530 535 540 Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 545 550 555 560 Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 565 570 575 Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 580 585 590 Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 595 600 605 Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 610 615 620 Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 625 630 635 640 Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 645 650 655 Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 660 665 670 Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly 675 680 685 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 690 695 700 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 705 710 715 720 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 725 730 735 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 740 745 750 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 755 760 765 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 770 775 780 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 785 790 795 800 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 805 810 815 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 820 825 830 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 835 840 845 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 850 855 860 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 865 870 875 880 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 885 890 895 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 900 905 910 Pro Gly Lys 915 <210> SEQ ID NO 17 <211> LENGTH: 2754 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60 cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120 ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180 gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240 gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300 gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360 attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420 attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480 gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540 gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600 gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660 actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720 tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780 tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840 atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900 aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960 cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020 gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080 aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140 ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200 actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260 agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320 acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380 caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440 tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500 ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560 gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620 gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680 gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740 gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800 ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860 actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920 actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980 catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040 gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100 gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160 ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220 cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280 ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340 caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400 tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460 ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520 ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640 accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700 gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754 <210> SEQ ID NO 18 <211> LENGTH: 917 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu 1 5 10 15 Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly 20 25 30 Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu 35 40 45 Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg 50 55 60 Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly 65 70 75 80 Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu 85 90 95 Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn 100 105 110 Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn 115 120 125 Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu 130 135 140 Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg 145 150 155 160 Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu 165 170 175 Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu 180 185 190 Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val 195 200 205 Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile 210 215 220 Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile 225 230 235 240 Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile 245 250 255 Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu 260 265 270 Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly 275 280 285 Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn 290 295 300 Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu 305 310 315 320 His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr 325 330 335 Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys 340 345 350 Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 355 360 365 Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 370 375 380 Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 385 390 395 400 Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 405 410 415 Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 420 425 430 Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 435 440 445 Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 450 455 460 Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 465 470 475 480 Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 485 490 495 Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 500 505 510 Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 515 520 525 Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 530 535 540 Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 545 550 555 560 Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 565 570 575 Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 580 585 590 Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 595 600 605 Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 610 615 620 Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 625 630 635 640 Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 645 650 655 Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 660 665 670 Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly 675 680 685 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe 690 695 700 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 705 710 715 720 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 785 790 795 800 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 865 870 875 880 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910 Leu Ser Leu Gly Lys 915 <210> SEQ ID NO 19 <211> LENGTH: 2754 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60 cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120 ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180 gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240 gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300 gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360 attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420 attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480 gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540 gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600 gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660 actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720 tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780 tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840 atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900 aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960 cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020 gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080 aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140 ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200 actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260 agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320 acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380 caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440 tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500 ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560 gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620 gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680 gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740 gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800 ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860 actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920 actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980 catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040 gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100 gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160 ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220 cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280 ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340 caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400 tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460 ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520 ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640 accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700 gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754 <210> SEQ ID NO 20 <211> LENGTH: 917 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu 1 5 10 15 Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly 20 25 30 Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu 35 40 45 Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg 50 55 60 Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly 65 70 75 80 Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu 85 90 95 Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn 100 105 110 Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn 115 120 125 Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu 130 135 140 Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg 145 150 155 160 Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu 165 170 175 Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu 180 185 190 Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val 195 200 205 Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile 210 215 220 Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile 225 230 235 240 Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile 245 250 255 Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu 260 265 270 Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly 275 280 285 Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn 290 295 300 Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu 305 310 315 320 His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr 325 330 335 Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys 340 345 350 Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp 355 360 365 Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe 370 375 380 Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp 385 390 395 400 Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro 405 410 415 Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr 420 425 430 Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr 435 440 445 Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser 450 455 460 Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu 465 470 475 480 Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro 485 490 495 Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile 500 505 510 Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu 515 520 525 Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr 530 535 540 Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys 545 550 555 560 Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro 565 570 575 Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile 580 585 590 Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val 595 600 605 Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val 610 615 620 Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg 625 630 635 640 Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg 645 650 655 Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala 660 665 670 Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly 675 680 685 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 690 695 700 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 705 710 715 720 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 785 790 795 800 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 865 870 875 880 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910 Leu Ser Leu Gly Lys 915 <210> SEQ ID NO 21 <211> LENGTH: 2748 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60 tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120 gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180 gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240 gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300 ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360 tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420 cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480 ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540 tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600 attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660 cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720 gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780 gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840 tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900 agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960 gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020 gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080 ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140 ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200 ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260 gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320 tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380 ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440 accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500 actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560 tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620 ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680 agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740 ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800 ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860 agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920 gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980 gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040 gaagcctcct ccacgttctc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100 gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160 atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220 gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280 gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340 tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400 gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460 ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520 tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580 accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640 gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700 cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748 <210> SEQ ID O 22 <211> LENGTH 915 <212> TYPE PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe 355 360 365 Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val 370 375 380 Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser 385 390 395 400 Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val 405 410 415 Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp 420 425 430 Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr 435 440 445 Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe 450 455 460 Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu 465 470 475 480 Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe 485 490 495 Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu 500 505 510 Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr 515 520 525 His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg 530 535 540 Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg 545 550 555 560 Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val 565 570 575 Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu 580 585 590 Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr 595 600 605 Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro 610 615 620 Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn 625 630 635 640 Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu 645 650 655 Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe 660 665 670 Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly 675 680 685 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 690 695 700 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 705 710 715 720 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 725 730 735 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 740 745 750 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 755 760 765 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 770 775 780 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 785 790 795 800 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 805 810 815 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 820 825 830 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 835 840 845 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 850 855 860 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 865 870 875 880 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 885 890 895 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 900 905 910 Pro Gly Lys 915 <210> SEQ ID NO 23 <211> LENGTH: 2754 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60 tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120 gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180 gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240 gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300 ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360 tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420 cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480 ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540 tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600 attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660 cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720 gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780 gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840 tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900 agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960 gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020 gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080 ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140 ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200 ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260 gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320 tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380 ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440 accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500 actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560 tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620 ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680 agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740 ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800 ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860 agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920 gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980 gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040 gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100 gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160 ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220 cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280 ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340 caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400 tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460 ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520 ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640 accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700 gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754 <210> SEQ ID NO 24 <211> LENGTH: 917 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 24 Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe 355 360 365 Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val 370 375 380 Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser 385 390 395 400 Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val 405 410 415 Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp 420 425 430 Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr 435 440 445 Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe 450 455 460 Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu 465 470 475 480 Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe 485 490 495 Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu 500 505 510 Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr 515 520 525 His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg 530 535 540 Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg 545 550 555 560 Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val 565 570 575 Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu 580 585 590 Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr 595 600 605 Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro 610 615 620 Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn 625 630 635 640 Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu 645 650 655 Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe 660 665 670 Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly 675 680 685 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe 690 695 700 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 705 710 715 720 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 785 790 795 800 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 865 870 875 880 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910 Leu Ser Leu Gly Lys 915 <210> SEQ ID NO 25 <211> LENGTH: 2754 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60 tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120 gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180 gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240 gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300 ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360 tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420 cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480 ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540 tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600 attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660 cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720 gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780 gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840 tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900 agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960 gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020 gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080 ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140 ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200 ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260 gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320 tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380 ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440 accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500 actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560 tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620 ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680 agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740 ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800 ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860 agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920 gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980 gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040 gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100 gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160 ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220 cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280 ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340 caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400 tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460 ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520 ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640 accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700 gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754 <210> SEQ ID NO 26 <211> LENGTH: 917 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe 355 360 365 Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val 370 375 380 Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser 385 390 395 400 Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val 405 410 415 Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp 420 425 430 Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr 435 440 445 Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe 450 455 460 Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu 465 470 475 480 Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe 485 490 495 Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu 500 505 510 Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr 515 520 525 His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg 530 535 540 Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg 545 550 555 560 Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val 565 570 575 Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu 580 585 590 Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr 595 600 605 Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro 610 615 620 Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn 625 630 635 640 Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu 645 650 655 Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe 660 665 670 Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly 675 680 685 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 690 695 700 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 705 710 715 720 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 725 730 735 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 740 745 750 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 755 760 765 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 770 775 780 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 785 790 795 800 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 805 810 815 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 820 825 830 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 835 840 845 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 850 855 860 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 865 870 875 880 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 885 890 895 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 900 905 910 Leu Ser Leu Gly Lys 915 <210> SEQ ID NO 27 <211> LENGTH: 177 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 Met Glu Ile Cys Arg Gly Leu Arg Ser His Leu Ile Thr Leu Leu Leu 1 5 10 15 Phe Leu Phe His Ser Glu Thr Ile Cys Arg Pro Ser Gly Arg Lys Ser 20 25 30 Ser Lys Met Gln Ala Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe 35 40 45 Tyr Leu Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn 50 55 60 Val Asn Leu Glu Glu Lys Ile Asp Val Val Pro Ile Glu Pro His Ala 65 70 75 80 Leu Phe Leu Gly Ile His Gly Gly Lys Met Cys Leu Ser Cys Val Lys 85 90 95 Ser Gly Asp Glu Thr Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp 100 105 110 Leu Ser Glu Asn Arg Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser 115 120 125 Asp Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp 130 135 140 Phe Leu Cys Thr Ala Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn 145 150 155 160 Met Pro Asp Glu Gly Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp 165 170 175 Glu <210> SEQ ID NO 28 <211> LENGTH: 152 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp 1 5 10 15 Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala 20 25 30 Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val 35 40 45 Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys 50 55 60 Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu 65 70 75 80 Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys 85 90 95 Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu 100 105 110 Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp 115 120 125 Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr 130 135 140 Lys Phe Tyr Phe Gln Glu Asp Glu 145 150 

We claim:
 1. A method of treating neointimal hyperplasia in a subject in need thereof, comprising administering an interleukin-1 (IL-1) antagonist to the subject such that neointimal hyperplasia is treated.
 2. The method of claim 1, wherein the neointinal hyperplasia is restenosis.
 3. The method of claim 1, wherein the neointimal hyperplasia is atherosclerosis.
 4. The method of claim 1, wherein the neointimal hyperplasia is vascular access dysfunction.
 5. The method of claim 1, wherein the neointimal hyperplasia is caused by surgical stenting, angioplasty, or vascular grafting.
 6. The method of claim 1, wherein the IL-1 antagonist blocks IL-1 activity or expression.
 7. The method of claim 6, wherein the IL-1 antagonist is selected from the group consisting of an anti-IL-1 antibody or antibody fragment, an anti-IL-1R1 antibody or antibody fragment, an antiIL-1RAcp antibody or antibodyfragment, an IL-1 trap, IL-1Ra, an antisense molecule, an inhibitory ribozyme designed to catalytically cleave gene mRNA transcripts encoding IL-1α, IL-1β, IL-1R1, IL-1RAcp, and a short interfering RNA (siRNA) molecule.
 8. The method of claim 7, wherein the IL-1 trap comprises (i) one or more IL-1 receptor components or fragments thereof, (ii) one or more antibody or antibody fragments specific to an IL-1 ligand or an IL-1 receptor, or fragments thereof, or a combination of receptor components and antibody fragments, and (iii) a multimerizing component.
 9. The method of claim 8, wherein the multimerizing component is an immunoglobulin-derived domain.
 10. The method of claim 1, wherein the subject is a human.
 11. The method of claim 1, wherein the administration is subcutaneous, intramuscular, intranasal, intraarterial, intravenous, topical, transvaginal, transdermal, transanal administration or oral routes of administration.
 12. A pharmaceutical composition comprising an IL-1 antagonist and a pharmaceutically acceptable carrier.
 13. The pharmaceutical composition of claim 12, wherein the IL-1 antagonist blocks IL-1 activity or expression.
 14. The pharmaceutical composition of claim 13, wherein the IL-1 antagonist is selected from the group consisting of an anti-IL-1 antibody or antibody fragment, an anti-IL-1R1 antibody or antibody fragment, an antiIL-1RAcp antibody or antibody fragment, an IL-1 trap, IL-1 Ra, an antisense molecule, an inhibitory ribozyme designed to catalytically cleave gene mRNA transcripts encoding IL-1α, IL-1β, IL-1R1, IL-1RAcp, and a short interfering RNA (siRNA) molecule.
 15. The pharmaceutical composition of claim 14, wherein the IL-1 trap comprises (i) one or more IL-1 receptor components or fragments thereof, (ii) one or more antibody or antibody fragments specific to an IL-1 ligand or an IL-1 receptor, or fragments thereof, or a combination of receptor components and antibody fragments, and (iii) a multimerizing component.
 16. The pharmaceutical composition of claim 15, wherein the multimerizing component is an immunoglobulin-derived domain.
 17. A method of preventing neointimal hyperplasia in a subject in need thereof, comprising administering a cytokine antagonist to the subject such that neointimal hyperplasia is prevented.
 18. The method of claim 17, wherein the neointinal hyperplasia is restenosis, atherosclerosis, or vascular access dysfunction.
 19. The method of claim 18, wherein the neointimal hyperplasia is caused by surgical stenting, angioplasty, or vascular grafting.
 20. An article of manufacturing, comprising: (a) packaging material; and (b) a pharmaceutical gent contained within the packaging materi9al; wherein the pharmaceutical agent comprises at least one interleuking-1 (IL-1) trap of the invention and wherein the packaging material comprises a label or package insert which indicates the IL-1 trap can be used for the treatment of neointimal hyperplasia. 